A group of viruses known as retroviruses are of particular concern because they cause diseases that are potentially lethal to an infected host. Retroviruses are a subgroup of RNA viruses that replicate by a reverse transcription mechanism using DNA polymerase that converts viral RNA into proviral DNA which becomes a part of the host cell DNA.
At the present time, several retroviruses are recognized as causative agents of infections in humans and animals. For example, human T cell lymphotropic viruses of type 1 and 2 (HTLV-1 and (HTLV-2) are known as the causative agents of T cell leukemia and debilitating neurological diseases.
The human immunodeficiency virus (HIV-1 & HIV-2) has been recognized as the causative agent of acquired immunodeficiency syndrome (AIDS) and AIDS related complex (ARC). Primary targets of these retroviruses called hereafter by a collective name HIV are believed to be T lymphocytes, responsible for the immune defense, although practically all of the human tissues and cell types can be susceptible to retroviral infection. Retroviral infection causes the disfunction of the immune system. As a result infected individuals may die from opportunistic infections such as pneumonia or from cancers which may be caused directly or indirectly by HIV infection. The final stage of retrovirus-associated malaise is AIDS that currently affects 14 million individuals all over the world. At the present time, most of the treatment for HIV patients is directed to the opportunistic infections or cancers that tend to occur as a infected person's T-cell count is reduced.
Currently available therapy that is directed against retroviruses is based primarily on the use of nucleoside analogues such as azidothymidine (AZT) that interfere with reverse transcription. AZT and other nucleoside analogues have been used in the treatment of AIDS and ARC. However, recent studies have shown that such drugs are inefficient and potentially harmful. Severe toxicity and eventual emergence of resistant viral strains is a major problem associated with the use of these drugs. In addition, long-term therapy with AZT was associated with increased incidence of malignant lymphomas.
In the prior art, cimetidine, ranitidine and famotidine were used as anti-ulcer drugs and their effect in suppressing gastric acid release is commonly associated with their property as an antagonist of histamine type 2 (H2) receptor. Compounds which are H2 antagonists were developed originally as substituted histamines. Cimetidine and related H2 antagonists are also believed to be involved in the modulation of immunity by acting either as inhibitors or enhancers of certain types of immune response. For this reason cimetidine was used in the immunotherapy of cancer in combination with other agents.
The present inventor has discovered that compounds that are antagonists of H2 receptors are useful in vitro as anti-HIV agents because they have a direct antiviral effect. The antagonists of H2 receptors can be also useful in vivo in the treatment of HIV infection. The most common commercially available forms of H2 antagonists are cimetidine, ranitidine and famotidine. There are no known reports in the scientific literature demonstrating specifically the direct antiviral effect of H2 antagonists.
Accordingly it is a primary object of this invention to provide a method for the inhibition of HIV in vitro.
It is also an object of this invention to provide a method for the prevention of the clinical manifestations of the symptoms of HIV infection in a host that has been exposed to HIV.
It is also an object of this invention to provide a method for the treatment of a host that is infected by HIV which involves lifelong therapy to suppress the in vivo replication of HIV. Preferably treatment should commence as soon as an exposure to HIV has been identified or at least prior the manifestation of clinical symptoms of HIV infection.
These and other objects of the invention will become apparent from a review of the appended specification.